WO2021104022A1 - Novel crystalline form of tropifexor and preparation method therefor - Google Patents

Novel crystalline form of tropifexor and preparation method therefor Download PDF

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WO2021104022A1
WO2021104022A1 PCT/CN2020/128097 CN2020128097W WO2021104022A1 WO 2021104022 A1 WO2021104022 A1 WO 2021104022A1 CN 2020128097 W CN2020128097 W CN 2020128097W WO 2021104022 A1 WO2021104022 A1 WO 2021104022A1
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crystal form
tropifexor
acid
ray powder
degrees
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PCT/CN2020/128097
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French (fr)
Chinese (zh)
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张�杰
廖伟龙
邝润桥
徐巾超
陈勇
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080080614.9A priority Critical patent/CN114728954B/en
Publication of WO2021104022A1 publication Critical patent/WO2021104022A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a new crystal form of Tropifexor and a preparation method thereof.
  • Tropifexor was originally developed by Novartis and then licensed to Pfizer for collaborative development. It is a non-steroidal FXR (farnesoid receptor) agonist, currently in clinical phase II of indications for NASH (non-alcoholic steatohepatitis), fatty liver and primary biliary cholangitis.
  • FXR farnesoid receptor
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is beneficial to the production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
  • the present invention obtains a new crystal form of the compound through a large number of experimental studies on the Tropifexor compound.
  • the new crystal form has the advantages of high solubility, good stability, low moisture absorption, simple preparation process and easy operation, etc., and has excellent properties in industrial production. Superiority.
  • an object of the present invention is to provide a new crystal form of Tropifexor and a preparation method thereof, which has good solubility and stability.
  • the present invention provides a new crystal form of Tropifexor: crystal form II.
  • the above-mentioned new crystal form of the present invention is studied, and it is found that the crystal form II has good properties in terms of stability and solubility, and can be used in the production of pharmaceutical preparations.
  • the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle : 12.6, 14.7, 15.0, 15.6, 17.0, 17.7, 18.2, 20.0, 22.6, 24.3, 24.9, 26.6, 28.3 and 28.8.
  • the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle : 5.7,6.9,9.1,10.0,11.1,12.0,12.6,14.4,14.7,15.0,15.6,16.4,17.0,17.4,17.7,18.2,20.0,20.5,20.9,21.6,22.6,23.1,23.8,24.3,24.9 , 25.3, 26.2, 26.6, 28.3 and 28.8.
  • the relative intensity of the peak at 17.4 degrees 2 ⁇ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystal form II has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
  • XRPD pattern X-ray powder diffraction pattern
  • the differential scanning calorimetry curve (DSC) of the crystal form II has an endothermic peak at 200°C to 250°C, and the peak temperature of the endothermic peak is 220°C to 225°C.
  • the crystalline form II has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
  • the crystalline form II has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 200°C, and the weight loss is about 0.5%.
  • TGA thermogravimetric analysis curve
  • the crystal form II has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
  • TGA pattern thermogravimetric analysis curve
  • the purity of the crystal form II is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to Tropifexor, the purity of the crystalline form II is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the Tropifexor crystal form II of the present invention can be used to treat diseases such as NASH, fatty liver and primary biliary cholangitis.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Tropifexor crystal form II and pharmaceutically acceptable auxiliary materials or excipients.
  • a therapeutically effective amount of Tropifexor crystal form II is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is prepared in a well-known manner in the pharmaceutical field.
  • the pharmaceutical composition or preparation can be used to treat diseases such as NASH, fatty liver, and primary biliary cholangitis.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-10% of the crystal form II of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-5% of the crystal form II based on the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-1% of the crystal form II of the total weight of the composition.
  • the present invention provides a pharmaceutical composition containing at least 0.1%-0.5% of the crystal form II based on the total weight of the composition.
  • the pharmaceutical composition provided by the present invention contains Tropifexor, and according to the mass ratio, at least 80% of the Tropifexor is the Tropifexor crystal form II. In some embodiments, a pharmaceutical composition contains Tropifexor, and according to a mass ratio, at least 90% of the Tropifexor is the Tropifexor crystal form II. In some embodiments, a pharmaceutical composition contains Tropifexor, wherein at least 95% of Tropifexor is the Tropifexor crystal form II according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and according to a mass ratio, at least 99% of Tropifexor is the Tropifexor crystal form II.
  • the purity of crystal form II in the pharmaceutical composition is at least 80%. In some embodiments, relative to Tropifexor, the purity of the crystalline form II in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the pharmaceutical composition containing Tropifexor crystal form II of the present invention can be used to prepare pharmaceutical preparations for NASH, fatty liver, primary biliary cholangitis and the like.
  • the pharmaceutical composition containing Tropifexor crystal form II of the present invention can be used in methods for treating diseases such as NASH, fatty liver, and primary biliary cholangitis.
  • the crystal form II provided by the present invention has good stability and solubility, is not easy to deliquesce under high humidity conditions, is convenient for long-term storage and placement of drugs, and can well avoid drug storage and crystal transformation during development, thereby avoiding bioavailability As well as the change of drug efficacy, it has strong economic value.
  • the present invention proposes a method for preparing the aforementioned Tropifexor crystal form II.
  • a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, mixing and stirring, and suspending at room temperature to precipitate crystals and collecting crystals to obtain crystal form II.
  • a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, mixing and stirring, volatilizing at room temperature until no more crystals are precipitated, removing the solvent, and collecting crystals to obtain crystal form II.
  • a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, stirring, and suspending at room temperature to precipitate crystals and collecting crystals to obtain crystal form II. In some embodiments, a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent and stirring, volatilizing at room temperature until no more crystals are precipitated, removing the solvent, and collecting crystals to obtain crystal form II .
  • the benzoic acid compound is anthranilic acid, m-aminobenzoic acid, p-aminobenzoic acid, salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, 2,4- At least one of dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, or p-aminosalicylic acid.
  • the good solvent is ethanol; when the mass is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of the Tropifexor to the good solvent is 1:2 ⁇ 1:100; more preferably 1:40 to 1:60.
  • the “crystal form” of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention
  • the “crystal form” of should be understood as falling within the protection scope of the present invention.
  • the present invention tests various parameters on a sample containing a certain "crystal form” that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different.
  • the experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C.
  • the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the mass unit is grams and the volume unit is milliliters.
  • RH means relative humidity
  • the room temperature is in the range of 20°C-40°C.
  • Figure 1 X-ray powder diffraction (XRPD) pattern of the crystal form II of the compound of formula (1).
  • FIG. 1 Differential scanning calorimetry (DSC) curve diagram of the crystalline form II of the compound of formula (1).
  • Figure 4 The isothermal adsorption equilibrium (DVS) curve diagram of the crystal form II of the compound of formula (1).
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytIIcal Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scanning mode, get the effective 2 ⁇ range of 3° ⁇ 40°.
  • the DSC measurement was performed in TA I Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/mIIn. Data was collected between room temperature and 300°C at a heating rate of 10°C/mIIn. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA UnIIversal AnalysIIs.
  • the TGA measurement was performed in TA I Instruments TM model Q500.
  • the operation step is to peel the empty crucible, take a solid sample of about 10 mg, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/mIIn between room temperature and 300°C under nitrogen purge, and record the spectrum.
  • the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions.
  • Deliquescence absorb enough water to form a liquid
  • weight gain by moisture-absorbing is not less than 15%
  • moisture absorption weight gain is less than 15% but not less than 2%
  • weight gain by moisture absorption is less than 2% but not less than 0.2%;
  • the weight gain is less than 0.2%.

Abstract

The present invention relates to the field of medicinal chemistry and provides a novel crystalline form of Tropifexor and a preparation method therefor. The crystalline form is crystalline form II. The XRPD pattern of the crystalline form II contains the following characteristic peaks of 2θ (error ±0.2 degrees): 5.7, 6.9, 9.1, 10.0, 11.1, 12.0, 14.4, 16.4, 17.4, 20.5, 20.9, 21.6, 23.1,23.8, 25.3, and 26.2 degrees. The crystalline form II has good solubility and stability, facilitates the storage, transfer, and operation in the production process, and is suitable for being prepared into preparations.

Description

Tropifexor的新晶型及其制备方法New crystal form of Tropifexor and its preparation method 技术领域Technical field
本发明属于药物化学领域，涉及Tropifexor的新晶型及其制备方法。The invention belongs to the field of medicinal chemistry, and relates to a new crystal form of Tropifexor and a preparation method thereof.
背景技术Background technique
Tropifexor最初由诺华研发，后授权给辉瑞进行合作开发。它是一种非甾体FXR(法尼醇受体)激动剂，目前均处于NASH(非酒精性脂肪性肝炎)、脂肪肝和原发性胆汁性胆管炎适应症的临床II期。Tropifexor was originally developed by Novartis and then licensed to Pfizer for collaborative development. It is a non-steroidal FXR (farnesoid receptor) agonist, currently in clinical phase II of indications for NASH (non-alcoholic steatohepatitis), fatty liver and primary biliary cholangitis.
Tropifexor结构如下式(1)所示：The structure of Tropifexor is shown in the following formula (1):
Figure PCTCN2020128097-appb-000001
Figure PCTCN2020128097-appb-000001
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于生产或利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is beneficial to the production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
目前没有文献公开Tropifexor的晶型，也没有相关的文献报道。At present, there is no literature that discloses the crystal form of Tropifexor, and there is no related literature report.
本发明通过对Tropifexor化合物进行大量实验研究，得到了该化合物的新晶型，该新晶型具有溶解度高，稳定性好，引湿性低，制备工艺简单易操作等优越性质，在工业生产中具有优越性。The present invention obtains a new crystal form of the compound through a large number of experimental studies on the Tropifexor compound. The new crystal form has the advantages of high solubility, good stability, low moisture absorption, simple preparation process and easy operation, etc., and has excellent properties in industrial production. Superiority.
发明内容Summary of the invention
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供Tropifexor新晶型及其制备方法，该晶型具有良好的溶解度和稳定性。The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, an object of the present invention is to provide a new crystal form of Tropifexor and a preparation method thereof, which has good solubility and stability.
根据本发明的一个方面，本发明提供了Tropifexor的新晶型：晶型II。According to one aspect of the present invention, the present invention provides a new crystal form of Tropifexor: crystal form II.
对本发明如上所述新晶型进行研究，发现晶型II在稳定性、溶解度等方面具有良好的性能，可用于制备药物制剂生产中。The above-mentioned new crystal form of the present invention is studied, and it is found that the crystal form II has good properties in terms of stability and solubility, and can be used in the production of pharmaceutical preparations.
所述晶型II，通过使用Cu-Kα辐射的X-射线粉末衍射仪，其X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.7,6.9,9.1,10.0,11.1,12.0,14.4,16.4,17.4,20.5,20.9,21.6,23.1,23.8,25.3 和26.2。Said crystal form II, by using an X-ray powder diffractometer using Cu-Kα radiation, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 5.7, 6.9 , 9.1, 10.0, 11.1, 12.0, 14.4, 16.4, 17.4, 20.5, 20.9, 21.6, 23.1,23.8, 25.3 and 26.2.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型II的X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：12.6,14.7,15.0,15.6,17.0,17.7,18.2,20.0,22.6,24.3,24.9,26.6,28.3和28.8。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle : 12.6, 14.7, 15.0, 15.6, 17.0, 17.7, 18.2, 20.0, 22.6, 24.3, 24.9, 26.6, 28.3 and 28.8.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型II的X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.7,6.9,9.1,10.0,11.1,12.0,12.6,14.4,14.7,15.0,15.6,16.4,17.0,17.4,17.7,18.2,20.0,20.5,20.9,21.6,22.6,23.1,23.8,24.3,24.9,25.3,26.2,26.6,28.3和28.8。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle : 5.7,6.9,9.1,10.0,11.1,12.0,12.6,14.4,14.7,15.0,15.6,16.4,17.0,17.4,17.7,18.2,20.0,20.5,20.9,21.6,22.6,23.1,23.8,24.3,24.9 , 25.3, 26.2, 26.6, 28.3 and 28.8.
在一些实施例中，Tropifexor晶型II的X-射线粉末衍射图中，在2θ为17.4度的峰的相对强度大于70％，或大于80％，或大于90％，或大于99％。In some embodiments, in the X-ray powder diffraction pattern of Tropifexor crystal form II, the relative intensity of the peak at 17.4 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
在一些实施例中，所述晶型II具有基本上如图1所示的X-射线粉末衍射图谱(XRPD图谱)。In some embodiments, the crystal form II has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
在一些实施例中，所述晶型II的差示扫描量热曲线(DSC)在200℃-250℃具有吸热峰，吸热峰的峰值温度在220℃-225℃。In some embodiments, the differential scanning calorimetry curve (DSC) of the crystal form II has an endothermic peak at 200°C to 250°C, and the peak temperature of the endothermic peak is 220°C to 225°C.
在一些实施例中，所述晶型II具有如图2所示的差示扫描量热曲线(DSC图谱)。In some embodiments, the crystalline form II has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
在一些实施例中，所述晶型II具有热重分析曲线(TGA)显示在30℃-200℃间有失重，失重量约为0.5％。In some embodiments, the crystalline form II has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 200°C, and the weight loss is about 0.5%.
在一些实施例中，所述晶型II具有基本上如图3所示的热重分析曲线(TGA图谱)。In some embodiments, the crystal form II has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
相对于Tropifexor，在一些实施例中，所述晶型II的纯度至少为70％，或至少80％，或至少90％，或至少95％，或至少99％。在一些实施例中，相对于Tropifexor，所述晶型II的纯度至少为85％，或至少90％，或至少95％，或至少99％。Relative to Tropifexor, in some embodiments, the purity of the crystal form II is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to Tropifexor, the purity of the crystalline form II is at least 85%, or at least 90%, or at least 95%, or at least 99%.
本发明所述的Tropifexor晶型II，可用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病。The Tropifexor crystal form II of the present invention can be used to treat diseases such as NASH, fatty liver and primary biliary cholangitis.
本发明的另一个目的在于提供包含治疗有效量的Tropifexor晶型II和药学上可接受的辅料或赋形剂的药物组合物。一般是将治疗有效量的Tropifexor晶型II与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。所述药物组合物或制剂可以用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病。Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Tropifexor crystal form II and pharmaceutically acceptable auxiliary materials or excipients. Generally, a therapeutically effective amount of Tropifexor crystal form II is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is prepared in a well-known manner in the pharmaceutical field. The pharmaceutical composition or preparation can be used to treat diseases such as NASH, fatty liver, and primary biliary cholangitis.
本发明提供的一种药物组合物，其可以含有至少为组合物的总重量的0.1％-10％的所述晶型II。本发明提供一种药物组合物，其可以含有至少为组合物的总重量的0.1％-5％的所述晶型II。本发明提供一种药物组合物，其可以含有至少为组合物的总重量的0.1％-1％的所述晶型II。在一些实施例中，本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-0.5％的所述晶型II。The present invention provides a pharmaceutical composition, which may contain at least 0.1%-10% of the crystal form II of the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-5% of the crystal form II based on the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-1% of the crystal form II of the total weight of the composition. In some embodiments, the present invention provides a pharmaceutical composition containing at least 0.1%-0.5% of the crystal form II based on the total weight of the composition.
本发明提供的一种药物组合物，含有Tropifexor，按照质量比，其中至少80％的Tropifexor为所述Tropifexor晶型II。在一些实施方式中，一种药物组合物，含有Tropifexor，按照质量比，其中至少90％的Tropifexor为所述Tropifexor晶型II。在一些实施方式中，一种药物组合物，含有Tropifexor，按照质量比，其中至少95％的Tropifexor为所述Tropifexor晶型II。在一些实施方式中，一种药物组合物，含有Tropifexor， 按照质量比，其中至少99％的Tropifexor为所述Tropifexor晶型II。The pharmaceutical composition provided by the present invention contains Tropifexor, and according to the mass ratio, at least 80% of the Tropifexor is the Tropifexor crystal form II. In some embodiments, a pharmaceutical composition contains Tropifexor, and according to a mass ratio, at least 90% of the Tropifexor is the Tropifexor crystal form II. In some embodiments, a pharmaceutical composition contains Tropifexor, wherein at least 95% of Tropifexor is the Tropifexor crystal form II according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and according to a mass ratio, at least 99% of Tropifexor is the Tropifexor crystal form II.
相对于Tropifexor，在一些实施方式中，所述药物组合物中，晶型II的纯度至少80％。在一些实施方式中，相对于Tropifexor，所述药物组合物中，晶型II的纯度至少85％，或至少90％，或至少95％，或至少99％。Relative to Tropifexor, in some embodiments, the purity of crystal form II in the pharmaceutical composition is at least 80%. In some embodiments, relative to Tropifexor, the purity of the crystalline form II in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
本发明所述的含有Tropifexor晶型II的药物组合物，可用于制备NASH、脂肪肝和原发性胆汁性胆管炎等的药物制剂。本发明所述的含有Tropifexor晶型II的药物组合物，可用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病的方法中。The pharmaceutical composition containing Tropifexor crystal form II of the present invention can be used to prepare pharmaceutical preparations for NASH, fatty liver, primary biliary cholangitis and the like. The pharmaceutical composition containing Tropifexor crystal form II of the present invention can be used in methods for treating diseases such as NASH, fatty liver, and primary biliary cholangitis.
本发明提供的晶型II，具有好的稳定性和溶解度，不易在高湿条件下潮解，方便药物长期贮存放置，能很好的避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变，具有很强的经济价值。The crystal form II provided by the present invention has good stability and solubility, is not easy to deliquesce under high humidity conditions, is convenient for long-term storage and placement of drugs, and can well avoid drug storage and crystal transformation during development, thereby avoiding bioavailability As well as the change of drug efficacy, it has strong economic value.
根据本发明的第二方面，本发明提出了一种制备前面所述的Tropifexor晶型II的方法。According to the second aspect of the present invention, the present invention proposes a method for preparing the aforementioned Tropifexor crystal form II.
一种制备Tropifexor晶型II的方法包括：将Tropifexor与苯甲酸类化合物混合，加入良溶剂混合搅拌，于室温下混悬，析出晶体，收集晶体，得到晶型II。A method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, mixing and stirring, and suspending at room temperature to precipitate crystals and collecting crystals to obtain crystal form II.
一种制备Tropifexor晶型II的方法包括：将Tropifexor与苯甲酸类化合物混合，加入良溶剂混合搅拌，室温下挥发至不再析出晶体，除去溶剂，收集晶体，得到晶型II。A method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, mixing and stirring, volatilizing at room temperature until no more crystals are precipitated, removing the solvent, and collecting crystals to obtain crystal form II.
在一些实施方式中，一种制备Tropifexor晶型II的方法包括：Tropifexor与苯甲酸类化合物混合，加入良溶剂搅拌，于室温下混悬，析出晶体，收集晶体，得到晶型II。在一些实施方式中，一种制备Tropifexor晶型II的方法包括：Tropifexor与苯甲酸类化合物混合，加入良溶剂搅拌，于室温下挥发至不再析出晶体，除去溶剂，收集晶体，得到晶型II。In some embodiments, a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent, stirring, and suspending at room temperature to precipitate crystals and collecting crystals to obtain crystal form II. In some embodiments, a method for preparing Tropifexor crystal form II includes: mixing Tropifexor with a benzoic acid compound, adding a good solvent and stirring, volatilizing at room temperature until no more crystals are precipitated, removing the solvent, and collecting crystals to obtain crystal form II .
上述制备Tropifexor晶型II的方法，所述的苯甲酸类化合物为邻氨基苯甲酸，间氨基苯甲酸，对氨基苯甲酸，水杨酸，间羟基苯甲酸，对羟基苯甲酸，2,4-二羟基苯甲酸，3,5-二羟基苯甲酸或对氨基水杨酸中的至少一种。In the above method for preparing Tropifexor crystal form II, the benzoic acid compound is anthranilic acid, m-aminobenzoic acid, p-aminobenzoic acid, salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, 2,4- At least one of dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, or p-aminosalicylic acid.
上述制备Tropifexor晶型II的方法，所述的良溶剂为乙醇；质量以克(g)计算，溶剂体积以毫升(mL)计算时，所述Tropifexor与良溶剂的质量体积比为1:2～1:100；更优选地为1:40～1:60。In the above method for preparing Tropifexor crystal form II, the good solvent is ethanol; when the mass is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of the Tropifexor to the good solvent is 1:2~ 1:100; more preferably 1:40 to 1:60.
本发明所述“晶型”可以以0.0001％-100％存在于样品中，因此，只要样品中含有即使痕量例如大于0.0001％，大于0.001％，大于0.001％或者大于0.01％的本发明所述的“晶型”都应当理解为落入本发明的保护范围内。为把本发明所述的“晶型”的各种参数描述得更清楚，本发明通过对含基本上纯净的某种“晶型”时的样品进行测试各种参数并对所述晶型进行表征和鉴别。The "crystal form" of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention The "crystal form" of should be understood as falling within the protection scope of the present invention. In order to describe the various parameters of the "crystal form" described in the present invention more clearly, the present invention tests various parameters on a sample containing a certain "crystal form" that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。基于公开的数字，每一个数字的数值有可能会出现1％，2％，或5％等差异。In the context of the present invention, regardless of whether the words "about" or "about" are used, all numbers disclosed herein are approximate values. Based on the public figures, the value of each figure may differ by 1%, 2%, or 5%.
所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另 一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。The differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different. The experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. The peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
在本发明中，计算质量体积比时，质量单位为克，体积单位为毫升。In the present invention, when calculating the mass-to-volume ratio, the mass unit is grams and the volume unit is milliliters.
在本发明中“RH”为相对湿度。In the present invention, "RH" means relative humidity.
在本发明中，室温在20℃-40℃范围。In the present invention, the room temperature is in the range of 20°C-40°C.
附图说明Description of the drawings
图1：式(1)化合物的晶型II的X-射线粉末衍射(XRPD)图。Figure 1: X-ray powder diffraction (XRPD) pattern of the crystal form II of the compound of formula (1).
图2：式(1)化合物的晶型II的差示扫描量热(DSC)曲线图。Figure 2: Differential scanning calorimetry (DSC) curve diagram of the crystalline form II of the compound of formula (1).
图3：式(1)化合物的晶型II的热重分析(TGA)曲线图。Figure 3: Thermogravimetric analysis (TGA) graph of the crystal form II of the compound of formula (1).
图4：式(1)化合物的晶型II的等温吸附平衡(DVS)曲线图。Figure 4: The isothermal adsorption equilibrium (DVS) curve diagram of the crystal form II of the compound of formula (1).
具体实施方式Detailed ways
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。The embodiments of the present invention are described in detail below. Examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals indicate the same or similar elements or elements with the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary, and are intended to explain the present invention, but should not be construed as limiting the present invention.
为了使本领域的技术人员更好的理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
实施例1 Tropifexor晶型II的制备方法Example 1 Preparation method of Tropifexor crystal form II
将60.3mg的Tropifexor和对氨基苯甲酸(13.7mg)混合后，加入乙醇(3.0ml)中，27℃搅拌得到澄清溶液后，室温静置约2天，析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末51.3mg。所得晶体经XPRD检测，确认为Tropifexor晶型II；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。After mixing 60.3 mg of Tropifexor and p-aminobenzoic acid (13.7 mg), they were added to ethanol (3.0 ml), stirred at 27° C. to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. Filter with suction and place in a drying box at 50°C and vacuum dry to constant weight to obtain 51.3 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically the same as that in Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.
实施例2 Tropifexor晶型II的制备方法Example 2 Preparation method of Tropifexor crystal form II
将60.3mg的Tropifexor和对羟基苯甲酸(13.8mg)混合后，加入乙醇(3.0ml)中，27℃搅拌得到澄清溶液后，室温静置约2天，析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末48.5mg。所得晶体经XPRD检测，确认为Tropifexor晶型II；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。After mixing 60.3 mg of Tropifexor and p-hydroxybenzoic acid (13.8 mg), they were added to ethanol (3.0 ml), stirred at 27° C. to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 48.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically the same as that in Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.
实施例3 Tropifexor晶型II的制备方法Example 3 Preparation method of Tropifexor crystal form II
将60.3mg的Tropifexor和水杨酸(13.8mg)混合后，加入乙醇(3.0ml)中，27℃搅拌得到澄清溶液后，室温静置约2天，析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末50.0mg。所得晶体经XPRD检测，确认为Tropifexor晶型II；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。After mixing 60.3 mg of Tropifexor and salicylic acid (13.8 mg), they were added to ethanol (3.0 ml), stirred at 27° C. to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. Filter with suction and place in a drying box at 50°C and vacuum dry to constant weight to obtain 50.0 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically the same as that in Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.
实施例4 Tropifexor晶型II的制备方法Example 4 Preparation method of Tropifexor crystal form II
将60.3mg的Tropifexor和2,4-二羟基苯甲酸(15.4mg)混合后，加入乙醇(3.0ml)中，27℃搅拌得到澄清溶液后，室温静置约2天，析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末49.5mg。所得晶体经XPRD检测，确认为Tropifexor晶型II；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。After mixing 60.3 mg of Tropifexor and 2,4-dihydroxybenzoic acid (15.4 mg), they were added to ethanol (3.0 ml) and stirred at 27° C. to obtain a clear solution. After standing at room temperature for about 2 days, a solid product was precipitated. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 49.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically the same as that in Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.
实施例5 Tropifexor晶型II的稳定性实验Example 5 Stability experiment of Tropifexor crystal form II
1)高温试验1) High temperature test
取本发明的Tropifexor晶型II样品敞口分别放置于60℃(温度偏差±5℃)/75％相对湿度(湿度偏差±5％)恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况实验结果如下表1。Take the Tropifexor crystal form II samples of the present invention and place them in a constant temperature and humidity box at 60°C (temperature deviation ±5°C)/75% relative humidity (humidity deviation ±5%), and then place them at 5, 10, and 15 respectively. About 10 mg of the above sample was taken every day, and the experimental results of the crystal form were tested as shown in Table 1.
表1晶型II稳定性研究Table 1 Stability study of crystal form II
Figure PCTCN2020128097-appb-000002
Figure PCTCN2020128097-appb-000002
上述结果显示：样品在高温60℃(温度偏差±5℃)/75％相对湿度(湿度偏差±5％)条件分别放置5天，10天，15天后，晶型不变，稳定性良好。The above results show that the sample is placed at a high temperature of 60°C (temperature deviation ±5°C)/75% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days, respectively, the crystal form does not change and the stability is good.
2)高湿试验2) High humidity test
取本发明的Tropifexor晶型II样品平铺置于称量瓶中，在25℃/92.5％相对湿度(湿度偏差±5％)恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况，实验结果如下表2。Take the Tropifexor crystal form II sample of the present invention and place it flat in a weighing bottle, place it in a constant temperature and humidity box at 25°C/92.5% relative humidity (humidity deviation ±5%), and then take it on 5, 10, and 15 days. The above sample is about 10 mg, and its crystal form is tested. The experimental results are shown in Table 2.
表2晶型II稳定性研究Table 2 Stability study of crystal form II
Figure PCTCN2020128097-appb-000003
Figure PCTCN2020128097-appb-000003
上述结果显示：样品在25℃/92.5％相对湿度(湿度偏差±5％)条件分别放置5天，10天，15天后，晶型不变，稳定性良好。The above results show that after the samples are placed at 25°C/92.5% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days, the crystal form remains unchanged and the stability is good.
3)光照试验3) Light test
取本发明的Tropifexor晶型II样品平铺置于称量瓶中，在可见光4500Lux±500Lux、紫外光1.7W*h/m2的恒温恒湿箱(25℃、RH60±5％)条件下放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况实验结果如下表3。Take the Tropifexor crystal form II sample of the present invention and place it flat in a weighing bottle, and place it in a constant temperature and humidity box (25°C, RH60±5%) with visible light 4500Lux±500Lux and ultraviolet light 1.7W*h/m2, Then, about 10 mg of the above sample was taken on 5, 10, and 15 days, and the crystal form was tested. The experimental results are shown in Table 3.
表3晶型II稳定性研究Table 3 Stability Study of Form II
Figure PCTCN2020128097-appb-000004
Figure PCTCN2020128097-appb-000004
上述结果显示：样品在可见光4500Lux±500Lux、紫外光1.7W*h/m 2的恒温恒湿箱(25℃、RH60±5％)条件下分别放置5天，10天，15天后，晶型不变，稳定性良好。 The above results show that the sample is placed in a constant temperature and humidity box (25℃, RH60±5%) of visible light 4500Lux±500Lux and ultraviolet light 1.7W*h/m 2 for 5 days, 10 days, and 15 days, the crystal form is not Change and good stability.
实施例6 Tropifexor晶型II的溶解度实验Example 6 Solubility experiment of Tropifexor crystal form II
预先称重烧瓶和搅拌子，精确称取Tropifexor新晶型II样品，分别加入瓶中，滴加水搅拌，至固体溶解停止加水。无目视可见的颗粒时，视为完全溶解。溶解后称重试管、搅拌子、和水溶液的总重量，计算出所加水的重量，然后计算出溶解度；水的密度按照1.00g/mL计算，测试晶型II样品在25℃或37℃的水中的溶解度，溶解度测试实验结果见表4。表4.Tropifexor晶型II的溶解度测试实验结果Weigh the flask and stir bar in advance, accurately weigh the samples of Tropifexor new crystal form II, add them to the bottle separately, add water dropwise and stir until the solids are dissolved and stop adding water. When there are no visible particles, it is regarded as completely dissolved. After dissolution, weigh the total weight of the test tube, stir bar, and aqueous solution, calculate the weight of the added water, and then calculate the solubility; the density of the water is calculated at 1.00g/mL, and the test crystal form II sample in 25℃ or 37℃ water The solubility and solubility test results are shown in Table 4. Table 4. Experimental results of solubility test of Tropifexor crystal form II
温度temperature Tropifexor晶型Tropifexor crystal form 溶解度Solubility
25℃25℃ 晶型IICrystal Form II 0.089mg/ml0.089mg/ml
37℃37°C 晶型IICrystal Form II 0.100mg/ml0.100mg/ml
由上表的测试溶解度数据可知：晶型II在水中具有很好的润湿性，溶解性好。From the test solubility data in the above table, it can be seen that the crystal form II has good wettability in water and good solubility.
实施例7 Tropifexor晶型II的引湿性分析Example 7 Analysis of moisture absorption of Tropifexor crystal form II
取50mg的Tropifexor晶型II固体，利用DVS仪器在25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。结果见图4。Take 50mg of Tropifexor crystal form II solid, use DVS instrument to change with relative humidity (0%-95.0%-0%) at 25.0℃, start from 0% relative humidity, and reach with a 10% relative humidity step change 95% relative humidity, and then a 10% relative humidity step change to 0% relative humidity. When the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions. The results are shown in Figure 4.
由图4可知：晶型II在DVS曲线湿度大于50％后引湿性缓慢上升，湿度为95％时，引湿增重仅为0.80％，说明晶型II具有较低的引湿性。It can be seen from Figure 4 that when the humidity of the DVS curve of the crystal form II is greater than 50%, the moisture attracting property increases slowly, and when the humidity is 95%, the moisture attracting weight gain is only 0.80%.
测试仪器及方法Testing equipment and methods
(1)X-射线粉末衍射(XRPD)研究(1) X-ray powder diffraction (XRPD) research
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytIIcal Empyrean X-射线衍射仪 上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2020128097-appb-000005
1.540598；Kα2
Figure PCTCN2020128097-appb-000006
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm.采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0168°的扫描步长在3～40°2θ范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data VIIewer和HIIghScore Plus分析和展示。 X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytIIcal Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage. The radiation source used is (Cu, kα, Kα1
Figure PCTCN2020128097-appb-000005
1.540598; Kα2
Figure PCTCN2020128097-appb-000006
1.544426; Kα2/Kα1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA. The beam divergence of X-rays, that is, the effective size of the X-ray confinement on the sample, is 10mm. Using θ-θ Continuous scanning mode, get the effective 2θ range of 3°～40°. Take an appropriate amount of sample in the circular groove of the zero background sample holder under ambient conditions (about 18°C ~ 32°C), press lightly with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample is used to generate a traditional XRPD pattern in the range of 3-40°2θ with a scanning step of 0.0168°. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data VIIewer and HIIghScore Plus.
采用上述条件，分别对实施例制备的晶型进行XRPD检测。Using the above conditions, the crystal forms prepared in the examples were tested by XRPD.
(2)差示扫描量热法(DSC)分析(2) Differential scanning calorimetry (DSC) analysis
DSC测量在TA IInstruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/mIIn吹扫。在室温到300℃之间以10℃/mIIn的加热速率收集数据。以吸热峰向下进行绘图,数据用TA UnIIversal AnalysIIs分析和展示。 The DSC measurement was performed in TA I Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/mIIn. Data was collected between room temperature and 300°C at a heating rate of 10°C/mIIn. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA UnIIversal AnalysIIs.
(3)热重分析(TGA)分析(3) Thermogravimetric analysis (TGA) analysis
TGA测量在TA IInstruments TM型号Q500中进行。操作步骤为空坩埚去皮，取固体样品约10mg、于去皮空坩埚内，铺匀即可。待仪器运行稳定后，在氮气吹扫下，室温到300℃之间以10℃/mIIn的加热速率收集数据，记录图谱。 The TGA measurement was performed in TA I Instruments TM model Q500. The operation step is to peel the empty crucible, take a solid sample of about 10 mg, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/mIIn between room temperature and 300°C under nitrogen purge, and record the spectrum.
(4)动态蒸汽吸附分析仪DVS(4)Dynamic vapor adsorption analyzer DVS
DVS测试等温吸附平衡曲线测试方法，仪器：DVS-IINTRIINSIIC，25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。DVS test isotherm adsorption equilibrium curve test method, instrument: DVS-IINTRIINSIIC, with relative humidity (0%-95.0%-0%) at 25.0℃, starting from 0% relative humidity, with 10% relative humidity steps The change reaches 95% relative humidity, and then a 10% relative humidity step change reaches 0% relative humidity. When the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions.
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录药物引湿性试验指导原则，实验条件：25±0.2℃，80％相对湿度)：Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2010 edition appendix drug hygroscopicity test guidelines, experimental conditions: 25±0.2℃, 80% relative humidity):
潮解：吸收足量水分形成液体；Deliquescence: absorb enough water to form a liquid;
极具引湿性：引湿增重不小于15％；Extremely moisture-absorbing: weight gain by moisture-absorbing is not less than 15%;
有引湿性：引湿增重小于15％但不小于2％；Has moisture absorption: moisture absorption weight gain is less than 15% but not less than 2%;
略有引湿性：引湿增重小于2％但不小于0.2％；Slight moisture absorption: weight gain by moisture absorption is less than 2% but not less than 0.2%;
无或几乎无引湿性：引湿增重小于0.2％。No or almost no hygroscopicity: the weight gain is less than 0.2%.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例 或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structures, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without mutual contradiction.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. A person of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.

Claims (11)

  1. Tropifexor的晶型II，其特征在于，使用Cu-Kα辐射，以2θ(误差±0.2度)表示的X射线粉末衍射光谱，晶型II的X-射线粉末衍射图中在2θ为5.7,6.9,9.1,10.0,11.1,12.0,14.4,16.4,17.4,20.5,20.9,21.6,23.1,23.8,25.3和26.2度的位置有衍射峰。The crystal form II of Tropifexor is characterized by using Cu-Kα radiation and an X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees). The X-ray powder diffraction pattern of the crystal form II is 5.7,6.9 in 2θ. There are diffraction peaks at 9.1, 10.0, 11.1, 12.0, 14.4, 16.4, 17.4, 20.5, 20.9, 21.6, 23.1,23.8, 25.3 and 26.2 degrees.
  2. 权利要求1所述的Tropifexor的晶型II，晶型II的X-射线粉末衍射图中在2θ为12.6,14.7,15.0,15.6,17.0,17.7,18.2,20.0,22.6,24.3,24.9,26.6,28.3和28.8度的位置有衍射峰；或晶型II的X-射线粉末衍射图中在2θ为5.7,6.9,9.1,10.0,11.1,12.0,12.6,14.4,14.7,15.0,15.6,16.4,17.0,17.4,17.7,18.2,20.0,20.5,20.9,21.6,22.6,23.1,23.8,24.3,24.9,25.3,26.2,26.6,28.3和28.8度的位置有衍射峰；或晶型II的X-射线粉末衍射图如图1所示。The crystal form II of Tropifexor according to claim 1, the X-ray powder diffraction pattern of the crystal form II in 2θ is 12.6, 14.7, 15.0, 15.6, 17.0, 17.7, 18.2, 20.0, 22.6, 24.3, 24.9, 26.6, There are diffraction peaks at 28.3 and 28.8 degrees; or the 2θ of the X-ray powder diffraction pattern of Form II is 5.7, 6.9, 9.1, 10.0, 11.1, 12.0, 12.6, 14.4, 14.7, 15.0, 15.6, 16.4, 17.0 There are diffraction peaks at, 17.4, 17.7, 18.2, 20.0, 20.5, 20.9, 21.6, 22.6, 23.1,23.8, 24.3, 24.9, 25.3, 26.2, 26.6, 28.3 and 28.8 degrees; or X-ray powder of crystal form II The diffraction pattern is shown in Figure 1.
  3. 权利要求1所述的Tropifexor的晶型II，晶型II的热重分析曲线显示在30℃-200℃间有失重，失重量约为0.5％。The crystalline form II of Tropifexor according to claim 1, and the thermogravimetric analysis curve of the crystalline form II shows a weight loss between 30°C and 200°C, and the weight loss is about 0.5%.
  4. 权利要求1所述的Tropifexor的晶型II，晶型II的纯度至少70％。The crystal form II of Tropifexor according to claim 1, and the purity of the crystal form II is at least 70%.
  5. 一种制备权利要求1-4任一所述的Tropifexor的晶型II的方法，包括：Tropifexor与苯甲酸类化合物混合，再加入良溶剂搅拌，加热至完全溶解后，室温下混悬，析出晶体，收集晶体，得到晶型II；或Tropifexor与苯甲酸类化合物混合，再加入良溶剂搅拌，加热至完全溶解后，室温下挥发至不再析出晶体，收集晶体，除去溶剂，得到晶型II；其中，所述的苯甲酸类化合物为邻氨基苯甲酸，间氨基苯甲酸，对氨基苯甲酸，水杨酸，间羟基苯甲酸，对羟基苯甲酸，2,4-二羟基苯甲酸，3,5-二羟基苯甲酸或对氨基水杨酸中的至少一种；所述的良溶剂为乙醇。A method for preparing the crystal form II of Tropifexor according to any one of claims 1-4, comprising: mixing Tropifexor with a benzoic acid compound, adding a good solvent and stirring, heating to complete dissolution, and suspending at room temperature to precipitate crystals , Collect crystals to obtain crystal form II; or mix Tropifexor with benzoic acid compounds, then add a good solvent and stir, heat to completely dissolve, volatilize at room temperature until no more crystals are precipitated, collect crystals, and remove the solvent to obtain crystal form II; Wherein, the benzoic acid compound is anthranilic acid, m-aminobenzoic acid, p-aminobenzoic acid, salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 3, At least one of 5-dihydroxybenzoic acid or p-aminosalicylic acid; the good solvent is ethanol.
  6. 根据权利要求5所述的方法，其特征在于所述Tropifexor与苯甲酸类化合物的摩尔比为1:0.5～1:2.0。The method according to claim 5, characterized in that the molar ratio of the Tropifexor to the benzoic acid compound is 1:0.5 to 1:2.0.
  7. 根据权利要求5所述的方法，其特征在于所述Tropifexor与良溶剂的质量体积比为1:2～1:100。The method according to claim 5, characterized in that the mass-volume ratio of the Tropifexor to the good solvent is 1:2 to 1:100.
  8. 一种药物组合物，包含治疗有效量的权利要求1-7任意一项中所述的晶型II及药学上可接受的辅料。A pharmaceutical composition comprising a therapeutically effective amount of the crystal form II described in any one of claims 1-7 and pharmaceutically acceptable excipients.
  9. 根据权利要求8所述的药物组合物，其中，按照质量比计，至少80％的Tropifexor为晶型II。The pharmaceutical composition according to claim 8, wherein at least 80% of Tropifexor is crystal form II in terms of mass ratio.
  10. 根据权利要求8或9所述的药物组合物，其特征在于，所述晶型II含量至少为组合物的总重量的0.1％-10％。The pharmaceutical composition according to claim 8 or 9, wherein the content of the crystal form II is at least 0.1%-10% of the total weight of the composition.
  11. 权利要求1-4任一所述的晶型或权利要求8-10任一所述的组合物在制备治疗NASH、脂肪肝和原发性胆汁性胆管炎的药物中的用途。Use of the crystal form according to any one of claims 1-4 or the composition according to any one of claims 8-10 in the preparation of a medicine for the treatment of NASH, fatty liver and primary biliary cholangitis.
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